Targeting Transcription Elongation Machinery for Breast Cancer Therapy

This project focuses on the important but under-studied role of the P-TEFb-dependent transcription elongation machinery in human breast cancer progression. Our goal is to test the hypothesis that transcription elongation is a key regulatory step in breast cancer development, and that targeting P-TEFb can be an effective strategy to block breast cancer progression. The positive transcription elongation factor b P-TEFb, composed of CDK9 and cyclin T, stimulates transcriptional elongation by RNA polymerase Pol II and regulates cell growth and differentiation. Recently, we demonstrated that P-TEFb also controls the expression of EMT regulators to promote breast cancer progression. In the nucleus, more than half of P-TEFb are sequestered in the inactive state 7SK snRNP complex. Our study supported by this grant showsthat the assembly of the 7SK snRNP is preceded by an intermediate complex between HEXIM1 and P-TEFb that allows transfer of the kinase active P-TEFb from Hsp90 to 7SK snRNP for its suppression. Downregulation of HEXIM1 locks PTEFb in the Hsp90 complex, keeping it in the active state to enhance breast cancer progression, but also rendering the cells highly sensitive to Hsp90 inhibition. Since HEXIM1 is often downregulated in human triple negative breast cancer TNBC, these cells are particularly sensitive to Hsp90 inhibition. Our study provides a mechanistic explanation for the increased sensitivity of TNBC to Hsp90 inhibition and therefore may provide a novel anti-cancer strategy for triple negative breast cancer.